the role of generic drugs in the treatment of viral...

The role of generic drugs in the

treatment of viral hepatitis

Dr Andrew Hill

University of Liverpool

United Kingdom

2nd International Meeting on Elimination of

Viral Hepatitis, Amsterdam, December 3rd 2016

What is the best

combination of DAAs

to mass produce?

2

7752/8133 33/34 281/361 39/41 24/2561/69

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

G1 G2 G3 G4 G5 G6

Pe

rce

nt

SV

RSofosbuvir + Ledipasvir ± RBV (12-24 wks)

Percentage SVR12, by Genotype

95% 97% 78% 88% 95% 96%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

G1 G2 G3 G4 G5 G6

Pe

rce

nt

SV

R

Grazoprevir + Elbasvir ± RBV ± SOF (12-18 wks)Percentage SVR12, by Genotype

95% 63%93% 74%80% 96%

24/251807/1904 24/30 118/127 5/8 26/35

1459/1575 21/22 296/316 64/70 5/5628/752

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

G1 G2 G3 G4 G5 G6

Pe

rce

nt

SV

RSofosbuvir + Daclatasvir ± RBV (12-24 wks)

Percentage SVR12, by Genotype

93% 95% 84% 94% 91% 100%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

G1 G2 G3 G4 G5 G6

Pe

rce

nt

SV

RSofosbuvir + Velpatasvir ± RBV (12-24 wks)

Percentage SVR12, by Genotype

97% 98% 81% 94% 95% 96%97% 98% 81% 94% 95% 96%97% 98% 81% 94% 95% 96%97% 98% 81% 94% 95% 96%97% 98% 81% 94% 95% 96%96% 99% 90% 100% 97% 100%

749/778 259/261 535/592 128/128 34/35 42/42

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

G1 G2 G3 G4 G5 G6

Pe

rce

nt

SV

R

Glecaprevir + Pibrentasvir (12-16 wks)Percentage SVR12, by Genotype

99% 100%99% 100%99% 95%

331/332 195/196 75/76 19/1926/26125/131

How cheaply can

medicines be

produced?

8

ActivePharmaceuticalIngredient

Raw drug substanceDatabase www.indiainfodrive.com shows exports of API from India to other countries, with costs per kilogram of API, for many drugs

9

Cost/kg of sofosbuvir API exports Jan 2015 to Jul 2016, weighted by size of shipment

Gotham D, Barber M, Fortunak J, Pozniak A, Hill A.

Abstract number A-792-0516-01639, presented at AIDS2016, Durban.

From API cost/kg to target price

API price/kg x grams per treatment course

+ $0.04 / tablet for excipients and tableting,

+ $0.35/month for formulation

x 10-50% profit margin

(10% for mass-produced drugs e.g. HIV, TB)

11Gotham D, Barber M, Fortunak J, Pozniak A, Hill A.

Abstract number A-792-0516-01639, presented at AIDS2016, Durban.

Target generic price of sofosbuvir

(12 weeks)

Gotham D, Barber M, Fortunak J, Pozniak A, Hill A.

Abstract number A-792-0516-01639, presented at AIDS2016, Durban.

50

.42

6 €

41

.68

0 €

40

.55

6 €

37

.93

6 €

13

.00

0 €

6.0

08

€

3.4

35

€

28

8 €

55

€

0 €

15.000 €

30.000 €

45.000 €

60.000 €

Ger

man

y

Fran

ce UK

Can

ada

Spai

n

Bra

zil

Au

stra

lia

Ind

ia

Targ

et

pri

ce in

Eu

ros

for

12

-we

ek

cou

rse

Sofosbuvir (Sovaldi)

German price: €50,426

Cost price: €55

Sofosbuvir prices:1. Canada (Quebec): http://www.ramq.gouv.qc.ca/SiteCollectionDocuments/liste_med/liste_med_2016_10_03_fr.pdf2. France: http://www.medecinsdumonde.org/actualites/presse/2016/09/29/mdm-soppose-au-brevet-sur-le-sovaldir-decision-le-5-octobre-2016

3. Germany: medizinfuchs.de4. Spain: http://politica.elpais.com/politica/2016/04/05/actualidad/1459873421_480033.html?id_externo_rsoc=TW_CC6. UK: British National Formulary 20167. Brazil: http://www.portaltransparencia.gov.br/despesasdiarias/empenho?documento=250005000012015NE8014938. Australia: Based on total annual government expenditure (AU$200 million) and 40,000 treated in 20169. India: http://hepcasia.com/wp-content/uploads/2016/03/31-Jan-2016-Indian-generic-sofosbuvir.pdf

Price of sofosbuvir by country (12 weeks)

Drug Current US price

(lowest)

Current lowest

Indian market

price

Target price

Sofosbuvir $49,680 $324 $62

Daclatasvir $50,653 $153 $14

SOF+LDV $56,700 $507 $96

SOF+VEL $74,760 - $181-216

HCV DAAs: Prices in USA and India versus Target

Gotham D, Barber M, Fortunak J, Pozniak A, Hill A. Rapidly falling costs for new hepatitis C direct-acting antivirals (DAAs): potential for universal access. Abstract number A-792-0516-01639, presented at AIDS2016, Durban.

Prices of HCV DAAs keep falling

SOF and DCV API now being exported from China for $800 per kg

This would lower the basic production price to $55 for 12 weeks of SOF/DCV

In Egypt, SOF/DCV is now available for $172 per 12 weeks (WHO 2016 report)

15

Entecavir for Hepatitis Bone year’s supply (0.2g)

Entecavir for Hepatitis B

cost per person/year by country

Entecavir (Baraclude)

US price: $15,111

Cost price: $36

Published in: Hill et al. Journal of Virus Eradication 2015.

Target versus Global lowest prices:

HIV, TB and Hepatitis

Mass produced HCV DAAs should fall

to <$90 per 12-week course

The new “$90 $90 $90” in 2017

There should be standard prices to treat HIV, Hep B/C and TB

< $90 per year to treat HIV: TDF/3TC/EFV

< $90 per year to treat Hepatitis B: TDF/3TC or ETV

< $90 for first-line treatment for TB

< $90 for 12-weeks course of HCV DAAs: SOF/DCV

TDF/3TC, efavirenz, entecavir and most TB drugs will be generic worldwide in 2017. Prices should then fall in all countries, close to Indian / South African levels.

<$90 price to cure Hepatitis C will only be in low and middle income countries

Could pharmaceutical

companies lower their

prices, but then treat

more people?

21

50

.42

6 €

41

.68

0 €

40

.55

6 €

37

.93

6 €

13

.00

0 €

6.0

08

€

3.4

35

€

28

8 €

55

€

0 €

15.000 €

30.000 €

45.000 €

60.000 €

Ger

man

y

Fran

ce UK

Can

ada

Spai

n

Bra

zil

Au

stra

lia

Ind

ia

Targ

et

pri

ce in

Eu

ros

for

12

-we

ek

cou

rse

Sofosbuvir prices:1. Canada (Quebec): http://www.ramq.gouv.qc.ca/SiteCollectionDocuments/liste_med/liste_med_2016_10_03_fr.pdf2. France: http://www.medecinsdumonde.org/actualites/presse/2016/09/29/mdm-soppose-au-brevet-sur-le-sovaldir-decision-le-5-octobre-2016

3. Germany: medizinfuchs.de4. Spain: http://politica.elpais.com/politica/2016/04/05/actualidad/1459873421_480033.html?id_externo_rsoc=TW_CC6. UK: British National Formulary 20167. Brazil: http://www.portaltransparencia.gov.br/despesasdiarias/empenho?documento=250005000012015NE8014938. Australia: Based on total annual government expenditure (AU$200 million) and 40,000 treated in 20169. India: http://hepcasia.com/wp-content/uploads/2016/03/31-Jan-2016-Indian-generic-sofosbuvir.pdf

Price of sofosbuvir by country (12 weeks)

If drug prices were lower,

could pharmaceutical

companies

still afford

to do R&D?

23

Gilead sales and profits

Cumulative sales of Sovaldi & Harvoni to

3Q 2016:

$40 billion

Profits in 2015:

$18 billion

Reference: Gilead quarterly product sales summaries

Gilead: $10 billion in tax avoidance

25

Washington Post, July 13 2016. Gilead is using Ireland as

a tax haven for global profits.

“The drug company that shocked the world

with its prices dodged $10 billion in taxes”

$10 billion is enough

money to treat 100 million

people with HCV, at the

cost price of $100 each

https://www.washingtonpost.com/news/wonk/wp/2016/07/13/maker-of-84000-drug-avoided-10-billion-in-u-s-taxes-report-says/

Pharma profits and tax avoidanceMain tax havens: Bermuda, Cayman Islands, BVI, Bahamas, Luxembourg, Ireland

26

Company Profits held

offshore

US Taxes

Avoided

Pfizer $69 billion $20 billion

Merck $57 billion $16 billion

Johnson & Johnson $51 billion $14 billion

Amgen $26 billion $9 billion

Abbott $24 billion $7 billion

BMS $24 billion $7 billion

Source: Citizens for Tax Justice, 2016. http://gormanandjoneslaw.com/offshore-tax-havens/http://america.aljazeera.com/articles/2015/3/12/obama-gambit-for-corporate-cayman-cash.html

Options if drugs still patented -

Voluntary licenses

Some pharmaceutical companies allow cheap generics to be sold in certain low and middle income countries, with voluntary licenses. However:

1. China, South America, Russia and Eastern European countries are not included in most of these agreements. As a result, prices in these countries can be unaffordable

2. Other countries may have voluntary licenses but if the company does not register the drug for regulatory approval, then the drug cannot be accessed

3. Merck and AbbVie have no voluntary licenses for their Hepatitis C treatments.

Sofosbuvir voluntary license coverage

A new option for access to treatment:

HIV and Hepatitis C buyers clubs

There are many companies willing to export generic PrEPand DAAs into Europe and North America

Several generic ARVs are already approved by the US Food and Drug Administration and the World Health Organization.

Generic PrEP or DAAs can be bought online in 10 minutes. Prices are falling rapidly.

www.alldaychemist.com

www.iwantprepnow.co.uk

www.fixhepc.com

www.myhepc.info

Patented vs Generic drugs for HCV

Harvoni

€45,000Generic SOF/DCV

€900

Hepatitis C: https://www.youtube.com/watch?v=HBF5cf5zt9U

HIV: https://youtu.be/JXnaHYzyAq4

Routes of export: https://youtu.be/X1QSHkUAP50

The legal basis of personal importation

Article 60 of TRIPS - De Minimis Imports – states:

Members may exclude from the application of the above

provisions small quantities of goods of a non-commercial

nature contained in travellers' personal luggage or sent in

small consignments

In line with Article 60, most countries allow some

form of personal medication importation

Medicines are being sent from India, China, Egypt

and Bangladesh to countries all over the world

FixHepC Buyer’s Club

N = 438RVR: 85 %EOT: 99% SVR4: 89%[Poster 256 –HIV Glasgow 2016]

www.fixhepc.com

Hep C Treatment Without Borders

N = 151RVR: 74 %EOT: 93% SVR4: 96% SVR12: 96%

http://hepatitisctreatment.homestead.com/

34

South East Asia Buyer’s Club

N = 237RVR: 99%EOT: 99%SVR4: 100%SVR12: 92%[Poster 256 –HIV Glasgow 2016]

35

Russian Buyer’s Club

N = 213RVR: 85%EOT: 100%SVR4: 100%SVR12: 98%[Poster 261 –HIV Glasgow 2016]

$490 for

SOF/DCV,

12 weeks

Conclusions

Elimination of disease is only affordable if drugs can be accessed at low prices, within national health budgets

We need new approaches to funding mass treatment programmes for Hepatitis C in Europe:

“All you can Treat” pricing – unlimited treatments for a fixed price

Or

Lower fixed prices. Under €4000 per cure for Hepatitis C.

Most drugs are fundamentally cheap to produce, so pharmaceutical companies can still make large profits from selling to larger numbers of people at lower unit prices.

Conclusions

If pharmaceutical companies refuse to lower prices, we

need back-up mechanisms to ensure access:

• Compulsory licenses

• Buyers Clubs

• Windfall taxes on tax avoidance

Recovery of Gilead’s $10 billion in avoided tax alone would

provide sufficient funds to treat everyone with Hepatitis C

worldwide, at cost price of <$90 per person.